Imatinib base has the chemical name 4-[(4-methylpiperazin-1-yl)methyl]-N[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide and the following chemical structure.

Imatinib is marketed by Novartis as tablets of imatinib mesylate salt under the tradename Gleevec®. Gleevec® has been approved for the treatment of Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML), myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements, aggressive systemic mastocytosis, hypereosinophilic syndrome, chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, and malignant gastrointestinal stromal tumors.
U.S. Pat. No. 5,521,184 (“'184 patent”), also published as EP 0 564 409, describes the synthesis of imatinib base by taking up N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (II) and 4-(4-methylpiperazin-1-yl-methyl)benzoyl chloride (III) in pyridine and stifling the resulting solution under nitrogen at room temperature for 23 hours. (See '184 patent, col. 25, 11. 55-62 (example 21)). The resulting crude imatinib base (I) was then purified by column chromatography using methylene chloride:methanol:25% aqueous ammonia solution (95:5:1). (See id.). International Publication WO 99/03854 (“WO '854”) describes the synthesis of imatinib mesylate salt from imatinib freebase prepared by the process of the '184 patent. (See WO '854, pp. 18-19 (Example 1)). The process is illustrated in Scheme 1.

International Publication No. WO 2004/074502 (“WO '502”) analyzed the process of the '184 patent, and stated that it was unsatisfactory because, for example, the process was slow, gave rise to undesirable side products, involved tedious work up procedures, and produced low yield of imatinib base. (See WO '502, p. 2). WO '502 further states that use of pyridine as a reaction solvent was undesirable because it was difficult to remove residual traces of pyridine from the final product. (See id.).
WO '502 describes the synthesis of imatinib base by (i) reacting N-(2-methyl-5-aminophenyl-4-(3-pyridyl)-2-pyrimidine-amine (II) and 4-(4-methylpiperazin-1-yl-methyl)benzoyl chloride dihydrochloride (IIIa) in dimethyl formamide (“DMF”) at 70° C. for 15 hours to produce imatinib trihydrochloride monohydrate (Ia). The imatinib trihydrochloride monohydrate (Ia) is isolated from the reaction mixture by filtration and then basified in aqueous ammonia to produce imatinib free base (I). (See id. at pp. 17-18 (Examples 1 and 2)). This process is illustrated in Scheme 2.

International Publication No. WO 2003/066613 (“WO '613”) describes the synthesis of imatinib base by condensing 4-(3-pyridyl)-2-pyrimidine-amine (IV) and N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide (V) in the presence of a palladium catalyst in xylene under argon. (See WO '613, pp. 20-21 (Example 10)). WO '613 also describes the synthesis of imatinib base by the reaction of 3-amino-1-pyridin-3-yl-propenone (VI) and N-(3-guanidino-4-methylphenyl)-4-(4-methylpiperazin-1-ylmethyl)-benzamide (VII) in n-butanol at 150° C. for 5 hours. (See id. at p. 21 (Example 9)). These processes are illustrated in Scheme 3.

The methods described in WO '613 are also unsatisfactory for industrial scale production. Use of palladium catalyst is expensive, and toxic. Also use of high temperatures and inert atmosphere make these methods expensive and problematic for bulk scale productions.
International Publication No. WO 2004/108699 (“WO '699”) and U.S. Pat. No. 7,674,901 (“'901 patent”) disclose the synthesis of imatinib base by condensation of N-(2-methyl-5-aminophenyl-4-(3-pyridyl)-2-pyrimidine-amine (II) with 4-chloromethylbenzoyl chloride (VIII) in the presence of triethylamine in an organic solvent to form 4-(chloromethyl N-(4-methyl-3-[(4-3-pyridyl-2-pyrimidine]-amino)phenyl benzamide (IX), which is then reacted with N-methylpiperazine in an organic solvent to form imatinib base. (See WO '699, pp. 21-22 (Example 1); '901 patent, col. 16, 1. 17 to col. 17, 1. 32).

The methods described in WO '699 are also unsatisfactory for industrial scale production in view of the use of organic bases, such as triethyl amine, and organic solvents, such as chloroform and DMF, which may be difficult to remove from the final imatinib base product.
Accordingly, there is a need in the art for additional processes for synthesizing imatinib base that are suitable for use on an industrial scale.